This application addresses broad Challenge Area (03): Biomarker Discovery and Validation and specific Challenge Topic, 03-MH-101: Biomarkers in mental disorders. While Major Depressive Disorder (MDD) is prevalent and disabling, compelling recent data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study indicate that only about half of patients attain remission from MDD, even after multiple antidepressant medication trials.(Rush, Trivedi et al. 2006) Further, no biomarker has been validated which can select an effective treatment for such patients, presenting critical unmet intellectual and clinical challenges. The recent landmark finding of an markedly elevated level of monoamine oxidase A (MAO- A) in the brains of depressed patients with MDD compared to controls, using positron emission tomography (PET) with a C11 labeled monoamine oxidase inhibitor (MAOI), has provided an unparalleled opportunity to address these challenges (Meyer, Ginovart et al. 2006). It has long been known that MAOIs are effective for some patients with treatment-resistant MDD, although their side effect profile makes them highly unacceptable both to patients and physicians, severely curtailing their utility.(Thase, Frank et al. 1992;Nolen, Haffmans et al. 1993). We propose: 1) to replicate this study using PET scans 20 subjects with MDD, compared to 10 non-depressed controls, but extending it to patients with treatment-resistant depression (TRD);and 2) to explore the correlation of the brain MAO-A level biomarker to treatment outcome by treating the 20 PET-imaged TRD patients with an MAOI, hypothesizing that their MAOI response will be related to their level of MAO-A. Brain MAO-A is an ideal candidate biomarker for this study since it appears to be significantly abnormally elevated in MDD, yet it has a broad range of values even among depressed patients. Most importantly, the MAO-A biomarker is known to be the single pharmacologic target of the treatment, making it appear likely that outcome with MAOI treatment will be related to MAO-A. We will conduct this study in a center with a long and deep interest in treatment with MAOIs and in treatment-resistant depression, and with excellent capabilities and experience in PET imaging. If this pilot study showed this biomarker to be predictive of MAOI response, it would strongly support proposals for future studies. It would advance the neuroscience of mood disorders and generate the potential, for the first time, to scientifically select treatment for patients with TRD. PUBLIC HEALTH RELEVANCE: A critical unmet need in depression research is to validate a biomarker predictive of treatment response for patients with treatment-resistant depression. The recent finding of an elevated level of monoamine oxidase A in the brains of unselected patients with major depression compared to controls by positron emission tomography provides a unique opportunity for such a validation. We propose to replicate and extend this finding to patients with treatment-resistant depression, and explore the relationship of brain MAO-A levels to treatment outcome with a monoamine oxidase inhibitor in this difficult to treat population.